An IL-1β driven neutrophil-stromal cell axis fosters a BAFF-rich microenvironment in multiple myeloma

Jong, Madelon M.E. de; Fokkema, Cathelijne; Papazian, Natalie; Heusden, Teddie van; Vermeulen, Michael; Hoogenboezem, Remco M.; Beek, Gregory van; Tahri, Sabrin; Sanders, Mathijs A.; Woestijne, Pieter van de; Gay, Francesca; Moreau, Phillipe; Büttner‐Herold, Maike; Bruns, Heiko; Duin, Mark van; Broijl, Annemiek; Sonneveld, Pieter; Cupedo, Tom

doi:10.1101/2023.03.03.530773

Cited by 3 publications

(5 citation statements)

References 73 publications

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“…Considering the connection of iMSCs with MRD, it is worth reevaluating the role of BM stroma-induced drug resistance in MM cells by considering the contribution from the inflammatory state in the MSCs. Equally important is to examine their roles in modulating the immune microenvironment, as recently demonstrated in the iMSC-specific activation of neutrophils [62]. Establishing an in vitro model for iMSCs through cytokine stimulations such as IL-1β represents an important step to address this issue.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory Bone Marrow Mesenchymal Stem Cells in Multiple Myeloma: Transcriptional Signature and In Vitro Modeling

Wang,

Yi,

et al. 2023

Cancers

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Bone marrow mesenchymal stem cells (BM MSCs) play a tumor-supportive role in promoting drug resistance and disease relapse in multiple myeloma (MM). Recent studies have discovered a sub-population of MSCs, known as inflammatory MSCs (iMSCs), exclusive to the MM BM microenvironment and implicated in drug resistance. Through a sophisticated analysis of public expression data from unexpanded BM MSCs, we uncovered a positive association between iMSC signature expression and minimal residual disease. While in vitro expansion generally results in the loss of the iMSC signature, our meta-analysis of additional public expression data demonstrated that cytokine stimulation, including IL1-β and TNF-α, as well as immune cells such as neutrophils, macrophages, and MM cells, can reactivate the signature expression of iMSCs to varying extents. These findings underscore the importance and potential utility of cytokine stimulation in mimicking the gene expression signature of early passage of iMSCs for functional characterizations of their tumor-supportive roles in MM.

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Section: Discussionmentioning

confidence: 99%

Inflammatory Bone Marrow Mesenchymal Stem Cells in Multiple Myeloma: Transcriptional Signature and In Vitro Modeling

Wang,

Yi,

et al. 2023

Cancers

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“…While most of the studies have focused on the immune component 4–7 , mounting evidence suggests that endothelial cells (EC) and mesenchymal stem cells (MSC) also contribute to the survival and growth of myeloma PC through the production of cytokines and the release of extracellular vesicles 8,9 . Moreover, an enhanced inflammatory signature has been identified in MSC of patients with MM 10–12 . However, the role of the non-hematopoietic BM microenvironment in the transition from MGUS to MM remains less understood.…”

Section: Introductionmentioning

confidence: 99%

“…While most of the studies have focused on the immune component [4][5][6][7] , mounting evidence suggests that endothelial cells (EC) and mesenchymal stem cells (MSC) also contribute to the survival and growth of myeloma PC through the production of cytokines and the release of extracellular vesicles 8,9 . Moreover, an enhanced inflammatory signature has been identified in MSC of patients with MM [10][11][12] . However, the role of the non-hematopoietic BM microenvironment in the transition from MGUS to MM remains less understood.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Remodeling of the Stromal and Endothelial Microenvironment in MGUS to Multiple Myeloma Progression

Cenzano,

Cócera,

Bantan

et al. 2024

Preprint

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Despite therapeutic advancements, Multiple Myeloma (MM) remains an incurable disease. To characterize the role that deregulation of the Bone Marrow (BM) microenvironment may have in the transition from healthy to Monoclonal Gammopathy of Undetermined Significance (MGUS), and from MGUS to MM, we performed single-cell RNA sequencing (scRNA-seq) of mesenchymal stromal cells (MSC) and endothelial cells (EC) from two mouse models, BIcgamma and MIcgamma, that recapitulate the principal clinical, genetic, and immunological characteristics of MGUS and MM patients. Our results identify distinct transcriptional dynamics between MSC and EC. While EC acquires a stress state during MGUS, a proliferating and angiogenic profile characterizes MM. On the other hand, MSC compromised their differentiation potential, exhibiting a more inflammatory profile that initiates from the MGUS stage. Interestingly, we identified interferon (IFN)-related myeloma signature in malignant EC of the BIcgamma model, which is also expressed in MSC but not observed in the most aggressive MIcgamma model and can be identified in a subgroup of MM patients. The analysis of the MSC and EC interactions with PC revealed stage-specific interactions of relevance for angiogenesis, immunomodulation, and MM extravasation. Finally, the translational relevance of our results in humans was confirmed on MSC from newly diagnosed patients at different stages of the disease. In summary, these results indicate a remodeling of the non-hematopoietic BM microenvironment in myeloma progression, providing potential targets at the tumor-niche interface that may hold clinical significance and complement existing immunotherapies.

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“…The disease is characterized by significant genetic and genomic heterogeneity between patients and within individual patients 2,3 . Several studies have demonstrated the role of the BM microenvironment in the development and progression of MM and treatment resistance [4][5][6][7][8] . Various mechanisms have been implicated in the expansion and growth of malignant PC.…”

Section: Introductionmentioning

confidence: 99%

“…Various mechanisms have been implicated in the expansion and growth of malignant PC. For example, the release of matrix metalloproteinases (MMPs) facilitates invasion into nearby tissues and metastasis, or the secretion of interleukins promotes myeloma cell growth or inhibits immune function 7,9 . Moreover, the induction of neutrophil extracellular traps (NETs) formation by neutrophils, or the impairment of T cell function, allows tumor expansion 8,10 .…”

Section: Introductionmentioning

confidence: 99%

Bone Marrow Spatial Transcriptomics Reveals a Myeloma Cell Architecture with Dysfunctional T-Cell Distribution, Neutrophil Traps, and Inflammatory Signaling

Sudupe,

Muiños-Lopez,

Lopez-Perez

et al. 2024

Preprint

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Understanding the spatial organization of the bone marrow (BM) microenvironment at single-cell resolution constitutes a challenge in multiple myeloma (MM). Using formalin-fixed paraffin-embedded (FFPE) samples from the MIcγ1 mouse model of MM and aged-matched healthy YFPcγ1 mice, we performed spatial transcriptional profiling with Visium Spatial Gene Expression. A custom data-analysis framework that combines spatial with single-cell transcriptomic profiling defined the BM cellular composition and established specific cell relations, visualizing the spatial distribution of transcriptionally heterogeneous MM plasma cells (MM-PC). MM pathogenesis transcriptional programs were spatially delineated within the BM microenvironment. A high-to-low MM-PC density gradient spatially correlated with effector-to-exhausted T cell phenotype abundance. In this context, MM cells in high-density MM-PC areas coexisted with dendritic cells while displaced neutrophils to the tumor border. Increased neutrophil extracellular trap formation, IL-17-driven inflammatory signaling, and osteoclast differentiation were spatially delineated within the BM microenvironment. The spatial identification of different areas of BM and the interaction between malignant cells and their microenvironment were validated in FFPE BM biopsies from MM patients with varying degrees of MM-PC infiltration. In summary, spatial transcriptomics depicts the BM cellular architecture of MM and reveals deregulated mechanisms underlying MM intercellular communication.

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An IL-1β driven neutrophil-stromal cell axis fosters a BAFF-rich microenvironment in multiple myeloma

Cited by 3 publications

References 73 publications

Inflammatory Bone Marrow Mesenchymal Stem Cells in Multiple Myeloma: Transcriptional Signature and In Vitro Modeling

Inflammatory Bone Marrow Mesenchymal Stem Cells in Multiple Myeloma: Transcriptional Signature and In Vitro Modeling

Transcriptional Remodeling of the Stromal and Endothelial Microenvironment in MGUS to Multiple Myeloma Progression

Bone Marrow Spatial Transcriptomics Reveals a Myeloma Cell Architecture with Dysfunctional T-Cell Distribution, Neutrophil Traps, and Inflammatory Signaling

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